Fibrosis is the formation of excess fibrous tissues or scar tissue in an organ or a tissue. Fibrosis is a common pathophysiological response of tissues to chronic injury or long-term inflammation. There are many potential origins of this fibrosis. It can be induced by a disease (inherited or not), by side effects of a treatment (for example radiation or chemotherapy), by a toxic environment (for example smoking), or by an injury. It can affect different organs such as the skin or the lung.
Fibrosis induced generally the failure of the tissue of the organ that is affected. Fibrotic tissue is like a scar tissue, stiff, thick, and rigid. Sometimes, it can also swell. For example, in the lung, fibrosis lead to a shortness of breath particularly during exercise and dry and hacking cough, due to the abnormal expansion of the fibrosis lung.
Some examples of fibrosis are pulmonary fibrosis (lungs), cystic fibrosis (lung and digestive system), Crohn's Disease (intestine), scleroderma/systemic sclerosis (lungs or skin), arthrofibrosis (knee, shoulder, other joints), cutaneous fibrosis with hypertrophic or keloid scars
When the tissue concerned by this phenomenon is the skin, it is principally the wound healing process that is affected.
The natural wound healing is divided into three sequential phases; each phase is characterized by specific cellular activities: the inflammatory phase, the proliferative phase and the remodeling phase.
The first phase, called the inflammatory phase, begins minutes after injury. The blood vessels rupture induces the clot formation, composed mainly of fibrin and fibronectin. The clot fills partially the lesion and allows the migration of the inflammatory cells within the lesion. The inflammatory cells are recruited to debride the wound. Platelets secrete factors, such as growth factors or cytokines, which induce the recruitment of cells implicated in the wound healing (inflammatory cells such as neutrophils and macrophages, fibroblasts and endothelial cells).
The second phase is called the proliferative phase and corresponds to the development of the granulation tissue. Fibroblasts migrate into the wound area, proliferate and form a new provisional extracellular matrix by secreting extracellular matrix (ECM) proteins. Then endothelial cells migrate to promote the neovascularization or angiogenesis of the lesion. Inside the granulation tissue, fibroblasts activate and differentiate into myofibroblasts, presenting contractile properties thanks to their expression of alpha-smooth muscle actin (similar to that in smooth muscle cells). Myofibroblasts have a key role in wound healing as they provide the contraction of the wound. Finally, keratinocytes migrate from the wound edge, proliferate and differentiate to reconstitute the epidermis.
The last phase of the wound healing process appears after the wound closure. It corresponds to the remodeling of the granulation tissue. The granulation tissue is reorganized, type III collagen is replaced by type I collagen, as normal dermis is principally composed of type I collagen. During this phase, myofibroblasts in excess are eliminated by apoptosis. The last phase of the wound healing is long. One year after injury, the scar is remodeled; it gets less red and thinner.
However, this process is not only complex but fragile; it is susceptible to interruption or failure leading to the formation of chronic or non-healing wounds or formation of abnormal scars. Factors which may contribute to this include diseases (such as diabetes, venous or arterial disease), age, infection or tissue localization.
Role of Fibroblasts in Wound Healing
Fibroblasts are implicated in the process of wound healing, this involves several steps of differentiation from a quiescent fibroblast to a mobilized fibroblast that will transform into a myofibroblast and finally enter apoptosis.
In normal wound healing, fibroblasts get activated, and then differentiate into myofibroblasts presenting contractile properties thanks to their expression of alpha-smooth muscle actin (αSMA). Myofibroblasts are responsible for the deposit of extra cellular matrix and for the wound closure by moving closer the wound edges. In hypertrophic scar, keloid or fibrous wound healing, the activity of myofibroblasts persists and leads to tissue deformation, which is particularly evident, for example, in hypertrophic scars developed after burn injury. The aim of the present invention is to map, at the whole genome scale, the different genes that will be activated or deactivated during this process, and thus providing a molecular signature of abnormal healing leading to abnormal scar or fibrosis
Connective tissues represent a wide variety of physical structures and different functions: tendons, cartilage, bone, dermis, cornea, etc. . . . As organs and tissues have specific functions (for example, skin functions are protection, sensation and heat regulation), connective tissues constituting these tissues and organs have also precise functions provided by specific cell types. For example, in the papillar or reticular dermis collagen I, III and V, XIV, elastic fibers, perlecan or SPARC are found On the contrary, types III, IX, X collagens are found associated with aggregan and dermatan sulfate in tendons.
Fibroblasts are the main cells of connective (or mesenchymal) tissues, in which cells are surrounded by extracellular matrix (contrary to epithelium where they are jointed together). These fibroblasts are active in wound healing of damages organs, as they proliferate, differentiate in myofibroblast, secrete collagens and other specific ECM proteins and fibers composing the connective tissue of the organ, leading to the healing and reorganization of the tissue.
Myofibroblasts are defined as the primary source of the excessive ECM proteins deposition occurring during fibrosis. Resident myofibroblasts arise from a population of tissue specific fibroblasts that proliferate and undergo activation in response to injury, as it is the case in many organs such as skin, lungs, or kidney.
Fibrosis, Hypertrophic Scars and Keloids
Fibrosis is a common pathophysiological response of tissues to chronic injury. Fibrosis affects different organs such as the skin or the lung. Fibrosis is characterized by a differentiation of fibroblasts into myofibroblasts and an excessive accumulation of connective tissue. Fibrosis induces a loss of function of the organ and potentially the failure of the organ.
Hypertrophic, keloid or fibrous scars result from abnormal wound healing. These scars are characterized by an excessive deposit of ECM proteins, especially collagen. In these abnormal wounds, granulation tissue is hyper proliferative, due to an excess of myofibroblasts (<<Cellular and molecular pathology of HTS: basis for treatment.>> Armour A, Scott P G, Tredget E E. Wound Repair Regen. 2007 September-October; 15 Suppl 1:S6-17. Review. Erratum in: Wound Repair Regen. 2008 July-August; 16(4):582).
In normal wound healing, fibroblasts get activated, and then differentiate into myofibroblasts presenting contractile properties thanks to their expression of alpha-smooth muscle actin (αSMA). Myofibroblasts are responsible for the deposit of extra cellular matrix and for the wound closure by moving closer the wound edges. In hypertrophic scar, keloid or fibrous wound healing, the activity of myofibroblasts persists and leads to tissue deformation, which is particularly evident, for example, in hypertrophic scars developed after burn injury.
Hypertrophic and keloid scars are characterized by deposit of excessive amounts of collagen leading to a raised scar (more intense in keloids than in hypertrophic scars). They are formed most often at the sites of pimples, body piercings, cuts and burns.
Some hypertrophic scars are non-functional scars as they limit the function of the skin where they developed. They generate a loss of mobility of the scar zone and the neighboring zones, which can completely limit the movements (for example, elbow and mobility of the arm). They are mostly the result of burns of specific anatomical zones.
Thus, the treatment of the wound is especially adapted to the wound in its early stage if it presents a risk of developing an abnormal scar or failing to heal correctly. By enhancing or manipulating factors that contribute to wound healing it may therefore be possible to correct the process, thereby reducing the likely occurrence of a fibrosis, hypertrophic scar or keloid. If a tissue (of an organ for example) is susceptible of developing a fibrosis, the treatment of this tissue at an early stage is also of interest.
The present invention can improve the quality of a patient's life by ensuring that new wounds do not deteriorate into a fibrosis, hypertrophic scar or keloid and existing wounds can be treated in a way that actively promotes healing and by the way prevents the formation of fibrosis, hypertrophic scar or keloid.